Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma
Cancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing protein (NLRP) inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role o...
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| Format: | Article |
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MDPI AG
2020-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/9/2518 |
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| author | Zili Zhai Jenny Mae Samson Takeshi Yamauchi Prasanna K. Vaddi Yuko Matsumoto Charles A. Dinarello Dinoop Ravindran Menon Mayumi Fujita |
| author_facet | Zili Zhai Jenny Mae Samson Takeshi Yamauchi Prasanna K. Vaddi Yuko Matsumoto Charles A. Dinarello Dinoop Ravindran Menon Mayumi Fujita |
| author_sort | Zili Zhai |
| collection | DOAJ |
| description | Cancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing protein (NLRP) inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role of inflammasome sensor NLRP1 in acquired drug resistance to temozolomide (TMZ) in melanoma. The sensitivity of melanoma cells to TMZ was negatively correlated with the expression levels of <i>O</i><sup>6</sup>-methylguanine-DNA methyltransferase (MGMT), the enzyme to repair TMZ-induced DNA lesions. When MGMT-low human melanoma cells (1205Lu and HS294T) were treated with TMZ for over two months, MGMT was upregulated, and cells became resistant. However, the resistance mechanism was independent of MGMT, and the cells that acquired TMZ resistance showed increased NLRP1 expression, NLRP inflammasome activation, IL-1β secretion, and NF-κB activity, which contributed to the acquired resistance to TMZ. Finally, blocking IL-1 receptor (IL-1R) signaling with IL-1R antagonist decreased TMZ-resistant 1205Lu tumor growth in vivo. Although inflammation has been associated with drug resistance in various cancers, our paper is the first to demonstrate the involvement of NLRP in the development of acquired drug resistance. Because drug-tolerant cancer cells become cross-tolerant to other classes of cancer drugs, NLRP1 might be a suitable therapeutic target in drug-resistant melanoma, as well as in other cancers. |
| first_indexed | 2024-03-09T06:08:11Z |
| format | Article |
| id | doaj.art-3e938359ce654fec9c63e0442d54180b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T06:08:11Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3e938359ce654fec9c63e0442d54180b2023-12-03T12:01:26ZengMDPI AGCancers2072-66942020-09-01129251810.3390/cancers12092518Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human MelanomaZili Zhai0Jenny Mae Samson1Takeshi Yamauchi2Prasanna K. Vaddi3Yuko Matsumoto4Charles A. Dinarello5Dinoop Ravindran Menon6Mayumi Fujita7Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USACancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing protein (NLRP) inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role of inflammasome sensor NLRP1 in acquired drug resistance to temozolomide (TMZ) in melanoma. The sensitivity of melanoma cells to TMZ was negatively correlated with the expression levels of <i>O</i><sup>6</sup>-methylguanine-DNA methyltransferase (MGMT), the enzyme to repair TMZ-induced DNA lesions. When MGMT-low human melanoma cells (1205Lu and HS294T) were treated with TMZ for over two months, MGMT was upregulated, and cells became resistant. However, the resistance mechanism was independent of MGMT, and the cells that acquired TMZ resistance showed increased NLRP1 expression, NLRP inflammasome activation, IL-1β secretion, and NF-κB activity, which contributed to the acquired resistance to TMZ. Finally, blocking IL-1 receptor (IL-1R) signaling with IL-1R antagonist decreased TMZ-resistant 1205Lu tumor growth in vivo. Although inflammation has been associated with drug resistance in various cancers, our paper is the first to demonstrate the involvement of NLRP in the development of acquired drug resistance. Because drug-tolerant cancer cells become cross-tolerant to other classes of cancer drugs, NLRP1 might be a suitable therapeutic target in drug-resistant melanoma, as well as in other cancers.https://www.mdpi.com/2072-6694/12/9/2518melanomainflammasomeNLRP1acquired resistancechemotherapy |
| spellingShingle | Zili Zhai Jenny Mae Samson Takeshi Yamauchi Prasanna K. Vaddi Yuko Matsumoto Charles A. Dinarello Dinoop Ravindran Menon Mayumi Fujita Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma Cancers melanoma inflammasome NLRP1 acquired resistance chemotherapy |
| title | Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma |
| title_full | Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma |
| title_fullStr | Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma |
| title_full_unstemmed | Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma |
| title_short | Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma |
| title_sort | inflammasome sensor nlrp1 confers acquired drug resistance to temozolomide in human melanoma |
| topic | melanoma inflammasome NLRP1 acquired resistance chemotherapy |
| url | https://www.mdpi.com/2072-6694/12/9/2518 |
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